Oltipraz increases the expression rate of microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GST), intracellular oxidoreductases, thus increasing their levels in cells. Oltipraz has been known to protect the cellular tissue from radiation see, S. G. Kim, et al., Molecular Pharmacology, 51, 225-233, 1997; S. Y. Nam, et al., Radiation Research, 147, 613-620, 1997!. That is, it can be noted that the increase in intracellular expression rate of mEH and GST is closely related to the protection of cells from radiation. Further, it has been generally recognized that the increase in intracellular expression rate of mEH and GST is also related to the protection of human body from toxic substances see, Ansher et al., Hepatology, 3, 932-935, 1983; Lu & Miwa, Annual Review of Pharmacology and Toxicology, 20, 513-531, 1980!.
It has been reported that the tissue damage induced by toxic substances such as acetaminophen or carbon tetrachloride has a close relation with the activity of cytochrome P450 2E1 which metabolizes such toxic substances see, S. K. Kim, et al., J Pharmacol. Exp. Therap. 277, 1058, 1996!. Thus, when laboratory rats are treated with a pyridine, a cytochrome P450 2E1 derivative, serious hepatic damage occurs even at low concentration of carbon tatrachloride. Therefore, it has been anticipated that if the activity of cytochrome P450 2E1 can be effectively inhibited, the tissue damage to human organs (particularly, liver) due to toxic substances may be avoided and, for the same reason, human body may also be protected from oncogenic substances, radiation, antitumor chemotherapeutics, etc, to small intestine, colon, gall bladder, bronchus, pancreas, mammary gland and skin.
As one of the therapeutic agents, which are presently used in the clinical field for the prevention and treatment of hepatic diseases induced by toxic substances, malotilate has been shown to have a good effect of preventing and treating hepatic diseases induced by carbon tetrachloride and acetaminophen. In addition, it has been also recognized that diallyl sulfide and allicin as one of aromatic substances in garlic oil have the effect of inhibiting oncogenesis due to 1,2-dimethylhydrazine and protecting liver from hepatotoxicity of 1,2-dimethylhydrazine.
Given much technical knowledge in the conventional art, the present inventors have considered the possibility that the allylthio group may play an important role in protecting human organs from toxic substances or radiation, and by increasing the intracellular expression of mEH and GST, at the same time, effectively inhibits the activity of cytochrome P450 2E1 as mentioned above. Thus, we have extensively conducted a study to newly synthesize numerous compounds having allylthio group and to examine their pharmacological activities. As a result, we have identified that the compound of formula (I), as defined above, in which allylthio group as a pharmacologically active group is introduced into pyridazine nucleus and a substituent such as halogen, alkoxy, etc., is introduced into the para-position of allylthio group, can protect human tissues from radiation and active toxic substances by increasing the expression of mEH and GST, and at the same time, by inhibiting the expression of metabolic enzymes.